The goal of this research proposal is to further develop a potent oral vaccine platform that is reusable for different pathogens and can be manufactured more rapidly and at lower cost than currently available vaccine technology. Rapid production time and ease of distribution of a vaccine in pill form will provide for an effective countermeasure against influenza and other potential pandemic viruses. Studies funded by Vaxart's Phase 1 SBIR have demonstrated that an expressed Toll Receptor 3 ligand, given in conjunction with antigen expressed from a non-replicating adenovirus vector significantly augments the adaptive immune response to oral vaccination, and is protective against avian influenza challenge in large animals. An effective gene-based technology must overcome the major obstacles of pre-existing and vaccine-induced immunity to the vector if it is to be used as a general platform for multiple antigens or boosting. Our results demonstrate that the oral vaccine route effectively circumvents vaccine induced immunity problems that occur with injected vector vaccines, which will allow the vector backbone to be reused without loss of activity. In Phase II, we propose to further develop and test vaccine effectiveness, formulation and safety in preparation for clinical testing. In Aim 1 of this proposal we will test the effectiveness of our oral vaccine to protect against cross-clade avian influenza challenge. Aim 2 provides a formulation path for oral drug product development. Aim 3 validates an animal model for pre-clinical safety testing for an enterically delivered oral vaccine. Aims 4 and 5 test for the biodistribution pattern and safety profile of oral vaccine capsule administration in animals. Together, the results from these aims will provide the pre-clinical data required to begin clinical testing of Vaxart's oral avian flu vaccine. PUBLIC HEALTH RELEVANCE: Vaxart is developing a new oral vaccination technology, which can be used to rapidly develop and manufacture effective vaccines for use against emerging pathogens including new strains of influenza virus;the technology can shorten the time from identified influenza strain to released product from 7 months to 4 months. With our flexible oral vaccine technology, genes from any pathogen can be rapidly inserted into this vaccine backbone, and manufactured into a vaccine using a highly efficient, standardized, GMP process. In addition, a significant advantage to developing a vaccine in pill form is the ease of administration in emergency situations such as pandemic, and in regions of the world that lack sufficient medical personnel.